This invention relates to a novel series of chemical compounds useful as HIV protease inhibitors and to the use of such compounds as antiviral agents.
Acquired Immune Deficiency Syndrome (AIDS) is a relatively newly recognized disease or condition. AIDS causes a gradual breakdown of the body""s immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980""s, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus III (HTLV-III), now more commonly referred to as the human immunodeficiency virus or HIV.
HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell""s chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte cell which plays a vital role in the body""s immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases such as, among others, pneumocystic carini pneumonia, Karposis sarcoma, and cancer of the lymph system.
Although the exact mechanism of the formation and working of the HIV virus is not understood, identification of the virus has led to some progress in controlling the disease. For example, the drug azidothymidine (AZT) has been found effective for inhibiting the reverse transcription of the retroviral genome of the HIV virus, thus giving a measure of control, though not a cure, for patients afflicted with AIDS. The search continues for drugs that can cure or at least provide an improved measure of control of the deadly HIV virus.
Retroviral replication routinely features post-translational processing of polyproteins. This processing is accomplished by virally encoded HIV protease enzyme. This yields mature polypeptides that will subsequently aid in the formation and function of infectious virus. If this molecule processing is stifled, then the normal production of HIV is terminated. Therefore, inhibitors of HIV protease may function as anti-HIV viral agents.
HIV protease is one of the translated products from the HIV structural protein pol gene. This retroviral protease specifically cleaves other structural polypeptides at discrete sites to release these newly activated structural proteins and enzymes, thereby rendering the virion replication-competent. As such, inhibition of the HIV protease by potent compounds may prevent proviral integration of infected T-lymphocytes during the early phase of the HIV-1 life cycle, as well as inhibit viral proteolytic processing during its late stage. Additionally, the protease inhibitors may have the advantages of being more readily available, longer lived in virus, and less toxic than currently available drugs, possibly due to their specificity for the retroviral protease.
In accordance with this invention, there is provided a novel class of chemical compounds that can inhibit and/or block the activity of the HIV protease, which halts the proliferation of HIV virus, pharmaceutical compositions containing these compounds, and the use of the compounds as inhibitors of the HIV protease.
The present invention relates to compounds falling within formula (1) below, and pharmaceutically acceptable salts thereof, that inhibit the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2). These compounds are useful in the treatment of infection by HIV and the treatment of acquired immune deficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts, and the pharmaceutical compositions of the present invention can be used alone or in combination with other antivirals, immunomodulators, antibiotics or vaccines. Compounds of the present invention can also be used as prodrugs. Methods of treating AIDS, methods of treating HIV infection and methods of inhibiting HIV protease are disclosed.
The compounds of the present invention are of the formula (1): 
wherein:
Q1 and Q2 are independently selected from hydrogen and substituted and unsubstituted alkyl and aryl, and Q1 and Q2 may for a ring with G,
Q3 is selected from mercapto and substituted and unsubstituted alkoxyl, aryloxyl, thioether, amino, alkyl, cycloalkyl, saturated and partially saturated heterocycle, and aryl,
Q4-Q8 are independently selected from hydrogen, hydroxyl, mercapto, nitro, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted alkoxyl, aryloxyl, thioether, acyl, sulfinyl, sulfonyl, amino, alkyl, cycloalkyl, saturated and partially saturated heterocycle and aryl, and further wherein any one of Q4-Q8 may be a member of a spiro ring and any two of Q4-Q8 may together be members of a ring,
Y and G are independently selected from oxygen, xe2x80x94NH, xe2x80x94N-alkyl, sulfur, selenium, and two hydrogen atoms,
D is carbon or nitrogen,
E is carbon or nitrogen,
Q9 is selected from hydrogen, halogen, hydroxyl, mercapto, and substituted and unsubstituted alkoxyl, aryloxyl, thioether, amino, alkyl, and aryl, wherein Q9 may form part of a ring,
A is a carbocycle or heterocycle, which is optionally further substituted,
and B is a carbocycle or heterocycle, which is optionally further substituted,
or a pharmaceutically acceptable salt thereof.
The invention also relates to compounds of formula (1), wherein all variables are the same as those defined above for formula (1) with the exception of D, which is carbon or nitrogen, and is singly bonded to each of the adjacent ring atoms.
The invention more particularly relates to preferred compounds of formula (1) wherein:
at least one of Q1 and Q2 is substituted or unsubstituted alkyl and the other is as defined above,
Q3 is selected from thioether and aryl,
Q4-Q8 are independently selected from hydrogen, hydroxyl, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted acyl, alkoxyl, amino and alkyl, and further wherein any one or more of Q4-Q8 may form part of a ring,
Y and G are each oxygen,
D is nitrogen,
E is carbon or nitrogen,
Q9 is hydrogen,
A is a carbocycle or heterocycle that is an aromatic or partially saturated, 5-7 membered mono-ring, which is optionally further substituted,
and B is a heterocycle that is a saturated or partially saturated, 8-12 membered poly-ring, which is optionally further substituted,
or a pharmaceutically acceptable salt thereof.
The invention even more particularly relates to compounds of the formula (1) wherein:
one of Q1 and Q2 is substituted or unsubstituted alkyl, preferably t-butyl, and the other is hydrogen,
Q3 is selected from thioaryl and aryl, preferably thiophenyl and phenyl,
Q4 is alkyl, preferably methyl,
Q5 is hydroxyl or xe2x80x94Oxe2x80x94J, wherein J is a hydrolyzable group, or substituted or unsubstituted alkoxyl or amino,
Q6-Q8 are independently selected from hydrogen, hydroxyl, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted alkoxyl, acyl, amino and alkyl, and further wherein any one or more of Q6-Q8 may form part of a ring,
Y and G are each oxygen,
D is nitrogen,
E is carbon,
Q9 is-hydrogen,
A is a carbocycle that is an aromatic, 5-6 membered monocyclic ring, preferably phenyl, which is optionally further substituted,
and B is a heterocycle that is a saturated, 6-14 membered monocyclic or polycyclic ring, which is optionally further substituted, preferably of the formula: 
wherein M1 and M2 are independently selected from hydrogen, mercapto, hydroxyl, and substituted and unsubstituted thioether, alkyl, alkoxyl, aryloxyl, amino, five membered heterocycle and carbocycle, sulfinyl, sulfonyl, and acyl, and wherein M1 and M2 optionally form a ring having up to 10 members, wherein preferably M1 and M2 independently have from zero to eight non-hydrogen atoms;
or a pharmaceutically acceptable salt thereof.
Preferred compounds of the formula (1) include those wherein:
one of Q1 and Q2 is tertiary alkyl, preferably t-butyl, and the other is hydrogen,
Q3 is thiophenyl, phenyl, naphthyl, or thionaphthyl,
Q4 is methyl,
Q5 is hydroxyl, amino, or xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group,
Q6-Q8 are independently selected from hydrogen, hydroxyl, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted alkoxyl, acyl, amino and alkyl, and further wherein any one or more of Q6-Q8 may form part of a ring,
Y and G are each oxygen,
D is nitrogen,
E is carbon,
Q9 is hydrogen,
A is phenyl, which is optionally further substituted,
and B is a heterocycle that is a saturated, 9-10 membered bi-ring, preferably decahydroisoquinolinyl or octahydrothieno(3,2-c]pyridinyl,
or a pharmaceutically acceptable salt thereof.
According to certain embodiments, the portion of formula (1): 
is designated as Z or Z1 and/or the portion of formula (1): 
is designated as X or X1.
According to certain of those embodiments, the compounds have formula 1(A): 
wherein:
Z is a group having the structure: 
wherein:
a is 1, 2, 3, 4, and 5;
b is 1, or 2;
c is 1, or 2;
d is 1, 2, 3, or 4;
each R2 is independently hydrogen, hydroxy, thiol, halo, amino, C1-C4 alkylamino, di(C1-C4) alkylamino, nitro, carboxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halo (C1-C4) alkyl, hydroxy (C1-C4) alkyl, C1-C6 alkylthio (C1-C6) alkyl, C1-C4 alkoxycarbonyl, carbamoyl, N-(C1-C4) alkylcarbamoyl, C1-C4 alkylsulfonyl, N,N-di (C1-C4) alkylcarbamoyl, or C1-C4 alkylsulfonylamino;
A1 and A2 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R8)xe2x80x94;
A3 and A4 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
A5 and A6 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R9)xe2x80x94;
A7 and A8 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
R8 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
R1 is aryl, or xe2x80x94S-aryl;
X is a group having the structure: 
where:
R is hydrogen, C1-C4 alkyl, or xe2x80x94CH2-pyridyl;
R3 is a group having the structure: 
p is 4 or 5;
R4 at each occurrence is independently hydrogen, C1-C6 alkyl or hydroxy (C1-C4) alkyl; and
R5 and R6 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy (C1-C4) alkyl; with the provisos that:
(1) one of A1 and A2 must be xe2x80x94N(R8)xe2x80x94;
(2) A1 and A2 cannot both be xe2x80x94N(R8);
(3) A3 and A4 cannot both be xe2x80x94Nxe2x80x94;
(4) one of A5 and A6 must be xe2x80x94N(R9);
(5) A5 and A6 cannot both be xe2x80x94N(R9)xe2x80x94;
(6) A7 and A8 cannot both be xe2x80x94Nxe2x80x94;
or a pharmaceutically acceptable salt thereof.
Also, according to certain of those embodiments, the compounds have the formula 1(B): 
wherein:
R1 is aryl, or xe2x80x94S-aryl;
X1 is a group having the formula: 
R2 is hydrogen, halo, or C1-C4 alkyl;
R3 is a group having the structure: 
p is 4 or 5;
R4 at each occurrence is independently hydrogen, C1-C6 alkyl or hydroxy (C1-c4) alkyl; and
R5 and R6 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy (C1-C4) alkyl;
z1 is a group having the structure: 
where:
a is 1, 2, 3, 4, or 5;
b is 1, or 2;
c is 1, or 2;
d is 1, 2, 3, or 4;
each R7 is independently hydrogen, hydroxy, thiol, halo, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, nitro, carboxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, halo(C1-C4)alkyl, hydroxy (C1-C4)alkyl, C1-C4 alkylthio(C1-C4)alkyl, C1-C4 alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, C1-C4 alkylsulfonyl, N,N-di(C1-C4)alkylcarbamoyl, or C1-C4 alkylsulfonylamino;
A1 and A2 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R8)xe2x80x94;
A3 and A4 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
A5 and A6 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R9)xe2x80x94;
A7 and A8 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
R8 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
T2 is hydrogen, or C1-C4 alkyl;
with the provisos that:
(1) one of A1 and A2 must be xe2x80x94N(R8)xe2x80x94;
(2) A1 and A2 cannot both be xe2x80x94N(R8)xe2x80x94;
(3) A3 and A4 cannot both be xe2x80x94Nxe2x80x94;
(4) one of A5 and A6 must be xe2x80x94N(R9)xe2x80x94;
(5) A5 and A6 cannot both be xe2x80x94N(R9)xe2x80x94;
(6) A7 and A8 cannot both be xe2x80x94Nxe2x80x94;
or a pharmaceutically acceptable salt thereof.
Preferred species of the formula (1) are:
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarbaxamide and its pharmaceutically acceptable salts, especially methanesulfonic acid salt, and its prodrug analogs, wherein the 3xe2x80x3 hydroxy is converted to xe2x80x94Oxe2x80x94J, as defined above, especially the dihydrogen phosphate hydrochloride salt; and [6S-(6R*,3aS*,7aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl- 4xe2x80x2aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]-octahydro-thieno[3,2-c]pyridine-6-N-t-butylcarboxamide and its pharmaceutically acceptable salts, especially methanesulfonic acid salt, and its prodrug analogs, wherein the 3xe2x80x3 hydroxy is converted to xe2x80x94Oxe2x80x94J, as defined above.
The present invention further provides pharmaceutical formulations comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, such as a diluent or excipient.
The present invention further provides a method of treating AIDS comprising administering to a host or patient, such as a primate, an effective amount of a compound of the present invention.
The present invention further provides a method of inhibiting HIV replication comprising administering to an HIV infected cell, a cell susceptible to HIV infection or a host or patient, such as a primate, an effective amount of a compound of the present invention.